Please use this identifier to cite or link to this item:
http://hdl.handle.net/2381/32721
Title: | RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
Authors: | Lagah, S. Tan, I. L. Radhakrishnan, Priya Hirst, Robert A. Ward, J. H. O'Callaghan, C. Smith, S. J. Stevens, M. F. Grundy, R. G. Rahman, R. |
First Published: | 15-Jan-2014 |
Publisher: | Public Library of Science |
Citation: | PLoS One, 2014, 9 (1), e86187 |
Abstract: | BACKGROUND: Telomeric 3' overhangs can fold into a four-stranded DNA structure termed G-quadruplex (G4), a formation which inhibits telomerase. As telomerase activation is crucial for telomere maintenance in most cancer cells, several classes of G4 ligands have been designed to directly disrupt telomeric structure. METHODS: We exposed brain tumor cells to the G4 ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) and investigated proliferation, cell cycle dynamics, telomere length, telomerase activity and activated c-Myc levels. RESULTS: Although all cell lines tested were sensitive to RHPS4, PFSK-1 central nervous system primitive neuroectodermal cells, DAOY medulloblastoma cells and U87 glioblastoma cells exhibited up to 30-fold increased sensitivity compared to KNS42 glioblastoma, C6 glioma and Res196 ependymoma cells. An increased proportion of S-phase cells were observed in medulloblastoma and high grade glioma cells whilst CNS PNET cells showed an increased proportion of G1-phase cells. RHPS4-induced phenotypes were concomitant with telomerase inhibition, manifested in a telomere length-independent manner and not associated with activated c-Myc levels. However, anti-proliferative effects were also observed in normal neural/endothelial cells in vitro and ex vivo. CONCLUSION: This study warrants in vivo validation of RHPS4 and alternative G4 ligands as potential anti-cancer agents for brain tumors but highlights the consideration of dose-limiting tissue toxicities. |
DOI Link: | 10.1371/journal.pone.0086187 |
eISSN: | 1932-6203 |
Links: | http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086187 http://hdl.handle.net/2381/32721 |
Version: | Publisher Version |
Status: | Peer-reviewed |
Type: | Journal Article |
Rights: | Copyright © 2014 Lagah et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Appears in Collections: | Published Articles, Dept. of Infection, Immunity and Inflammation |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells..pdf | Published (publisher PDF) | 1.37 MB | Adobe PDF | View/Open |
Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.